Pharmaceutical formulations

Abstract

This invention relates to a pharmaceutical formulation and more particularly to one for an Active Pharmaceutical Ingredient (API) which is recognised under the Biopharmaceutical Classification System (BCS) as a Class I, II or III drug. In addition to the API it comprises a combination of gelling agents comprising: a primary gelling agent which is carrageenan, two secondary gelling agents, agar and alginate together with at least one divalent cation donator, a preservative, and water and optionally a thickening agent, sweetener(s) and flavouring.

Description

PHARMACEUTICAL FORMULATIONS

[0001] This invention relates to pharmaceutical formulations and more particularly to one’s for Active Pharmaceutical Ingredients (APIs) which are recognised under the Biopharmaceutical Classification System (BCS) as a Class I, Class II or Class III drug.BACKGROUND

[0002] APIs can be difficult to formulate as their properties differ from API to API. Two of the parameters that challenge a formulation chemist are an APIs solubility and its permeability. Accordingly, APIs are broadly defined as those falling into one of four classification types based on these two parameters. These four types are illustrated in Fig 1.

[0003] Class I APIs have high permeability and high solubility.a. An Example is Metoprolol.b. Class I compounds are well absorbed, and their absorption rate is usually higher than excretion.

[0004] Class II APIs have high permeability and low solubility.a. Examples include Ibuprofen and Naproxen.b. The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.

[0005] Class III APIs have low permeability and high solubility.a. An example is Cimetidine.b. The absorption is limited by the permeation rate, but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied.

[0006] Class IV APIs have low permeability and low solubility.a. An example is Bifonazole.b. These compounds have a poor bioavailability. Usually, they are not well absorbed over the intestinal mucosa and a high variability is expected.

[0007] The APIs are classified in BCS on the basis of solubility, permeability, and, also, dissolution.

[0008] Solubility class boundaries are based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 mL or less of aqueous media over the pH range of 1.0 to 7.5. The volume estimate of 250 mL is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water.

[0009] Permeability class boundaries are based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non-human systems capable of predicting drug absorption in humans can be used (such as in-vitro culture methods). A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose.

[0010] Dissolution class boundaries include an immediate release product, namely one which is rapidly dissolving, i.e. when no less than 85% of the labelled amount of the drug substance dissolves within 15 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM in a volume of 900 mL or less in the following media: 0.1 M HCI or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

[0011] Most oral formulations take the form of filled capsules or tablets. There is therefore a need to provide alternative dosage forms of many drugs, which dosage forms can be more readily taken by certain patient groups e.g. children, and the elderly.

[0012] Having a “base” formulation which is suitable for a number of different APIs would be advantageous in that it lowers regulatory hurdles and reduce costs in bringing “equivalents” to market.

[0013] Additionally, an API can also refer to isolated, purified or standardised versions of vitamins, minerals, herbal extracts or supplements that provide a therapeutic effect such as curing, treating or preventing disease. These APIs must meet strict quality and purity standards such as following Good Manufacturing Practice (GMP) and meeting specifications outlined in pharmacopeias’ like the United States Pharmacopeia (USP).

[0014] The dosage form may be used in human or animal health.

[0015] Of course, other formulation types are known, and Applicant has developed several drinkable gel-based formulations in areas such as glucose tolerance testing and for delivering nutraceuticals - see respectively: WO2017 / 075672, WO2019215641, WO2024028788 and WO2024134616.

[0016] Other background art identified includes:

[0017] WO 02 / 064120 A1 which discloses an edible gel containing two medical components; a first edible gel component is broken down in the stomach, and a second edible gel component is broken down in the intestinal tract.

[0018] US 2007 / 0053939 A1 which discloses a jelly preparation comprising a biguanide drug such as metformin hydrochloride or buformin hydrochloride, inorganic acids, and water-soluble polymers wherein the weight ratio of the inorganic acid to the biguanide drug is in the range of 0.01 to 2 and the pH of the solution before gelation is 4.0 or more.

[0019] US 2007 / 0128285 A1 which discloses a jellied pharmaceutical composition for oral administration containing a 5-HT3receptor antagonist, a gelatinizing agent and water, wherein the composition has a pH of 7 or less; and

[0020] CA 2619367 A1 which discloses a gel preparation for oral administration comprising an HMG-CoA reductase inhibitor, a gelling agent, a polymer compound, a buffering agent, a sweetening agent, a base and water, wherein the composition has a pH between 7 and 10.

[0021] However, there remains a need to develop pharmaceutical formulations which are easier to swallow or have other benefits e.g. improved shelf life, bioavailability, taste and / or texture. These, new formulations, like Applicants’ referenced formulations are drinkable gels, delivered in an amount of typically 20 to 50 mL, more preferably 30 to 50 mL (or g), which when sucked from e.g. a pouch, shear making them drinkable.

[0022] The term “drinkable” is herein interchangeable with drink, suck, suckable, squeeze, and squeezable.

[0023] “Drinkable” refers to mechanical disruption of the set gel to a flowable mass that is swallowable without chewing by the application of an external force that may include, but not be limited to, the application of a negative pressure applied to a nozzle, straw, or spout (sucking), a positive pressure applied to a container attached to or comprising a syringe, nozzle, straw, or spout (squeezing), stirring or scooping with a spoon from an open container.

[0024] In this regard Applicant has also developed a “base formulation” for BCS class II drugs - application number PCT / IB2024 / 054921, but it remains desirable to be able to formulate other BCS class drugs using a common approach rather than having many bespoke formulations.

[0025] It is an object of the present invention to provide alternative pharmaceutical formulations for difficult to formulate drugs, whether BCS Class I drugs, as exemplified by,for example, (1) Cetirizine, a Class II drug as exemplified by, for example, (2) Ibuprofen or a Class III drug as exemplified by, for example (3) Metformin.

[0026] Cetirizine is a second generation antihistamine, seehttps: / / en.wikipedia.org / wiki / Cetirizine.

[0027] Branded versions include Allacan, Piriteze, and Zyrtec.

[0028] Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation, see https: / / en.wikipedia.org / wiki / lbuprofen.

[0029] Branded versions include Advil, Motrin and Nurofen.

[0030] Metformin is the main first-line medication for the treatment of Type 2 diabetes, see https: / / en.wikipedia.org / wiki / Metformin.

[0031] Branded versions include Glucophage, Riomet, Fortamet, and Glumetza in the US and Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor in other parts of the world.

[0032] From a regulatory perspective it is possible to obtain registration for a new dosage form using an abridged process such as that provided by the FDA using 505(B)(2) regulatory pathways. See for example: https: / / www.fda.gov / media / 156350 / download incorporated by reference.BRIEF SUMMARY OF THE DISCLOSURE

[0033] In accordance with the present inventions there is provided a textured gel formulation, for Active Pharmaceutical Ingredients (APIs) spanning Biopharmaceutical Classification System (BCS) Class I, II and III, comprising:i) a Biopharmaceutical Classification System (BCS) Class I, II or III Active Pharmaceutical Ingredient (API), or a salt or solution thereof, ii) a primary gelling agent which is a carrageenan,iii) a first secondary gelling agent which is an alginate,iv) a second secondary gelling agent which is an agar,v) at least one cation donator,vi) a preservative,vii) at least one pH modifier, andviii) water.

[0034] In some embodiments the formulation further comprises one or more of:ix) one or more sweetener(s),x) an emulsifier,xi) an oil,xii) a flavouring, andxiii) a thickening agent.

[0035] The addition of a thickening agent, preferably xanthan gum in an amount by wt % of from 0.1 to 0.4%, proved to be desirable for embodiments where the gel showed a tendency for syneresis in storage, handling and / or shelf-life.

[0036] With drinkable gels, which contain water, syneresis can prove challenging, and indeed Applicant determined that for formulations comprising the 2 gelling agents in the amounts used in the 25 to 37mL (or g) embodiments it was desirable to further add a thickening agent, e.g. xanthan gum, in the amount 0.1 to 0.4% to address the syneresis.

[0037] Of course, alternative thickening agents might be used in appropriate amounts. Such alternative thickening agents include starch (e.g. arrowroot, corn starch, modified starch, potato starch, tapioca starch), gums (e.g. acacia gum, gum arabic, gellan gum, guar gum, locust bean gum,), as well as gelatin and cellulose derivatives (e.g. methylcellulose).

[0038] Non-limiting examples of textured formulations comprising APIs representative of different BCS classes include (by USAN naming) Cetirizine (a BCS Class I API), or a salt or solution thereof, Ibuprofen (a BCS Class II API), or a salt or solution thereof, and Metformin (a BCS Class III API), or a salt or solution thereof.

[0039] United States Adopted Name (USAN) is a non-proprietary name for a pharmaceutical drug that is assigned by the USAN Council. The same drug may appear under different brand names.

[0040] The terms “primary”, and “secondary” are used to denote the relative proportion (by weight percent) of the respective gelling agents such that the primary gelling agent (carrageenan) is present in the greatest amount and at least two secondary gelling agents (agar and alginate) are present in a lesser amount.

[0041] The two secondary gelling agents are present such that either can be present in an amount which is greater, lesser or equal to the other.

[0042] The primary agent is a carrageenan, more particularly kappa carrageenan.

[0043] Carrageenan’s are large, highly flexible molecules that form curling helical structures. This gives them the ability to form a variety of different gels at room temperature. They are widely used in the food and other industries as thickening and stabilizing agents.

[0044] All carrageenan are high-molecular-weight polysaccharides and are mainly made up of alternating 3- linked p-D-galactopyranose (G-units) and 4- linked a-D-galactopyranose (D-units) or 4-linked 3,6-anhydro-a-D-galactopyranose (DA-units), forming the disaccharide repeating unit.

[0045] There are three main commercial classes of carrageenan which differ in the degree of sulphation and have the following properties:• Kappa which forms strong, rigid gels in the presence of sodium and potassium ions.• lota which forms soft gels in the presence of calcium ions, and« Lambda which does not gel.

[0046] The secondary gelling agents are alginate and agar.

[0047] The alginates include:• Sodium alginate (NaC6H7O6),• Potassium alginate (KC6H7O6), and• Calcium alginate (CaC12H14O12).

[0048] Agar is an elastic, as opposed to plastic gel.

[0049] Agar is outstanding among hydrocolloids. Agar-agar gels can be formed in very dilute solutions, containing as little as 0.5% to 1.0% of agar-agar. These gels are rigid, brittle, have well defined shapes, as well as sharp melting and gelling points. Moreover, they clearly demonstrate the interesting phenomenon of syneresis (spontaneous extrusion of water through the surface of the gel), and hysteresis (temperature interval between melting and gelling temperatures). Gelling occurs at temperatures far below the gel melting temperature. A 1.5% solution of agar-agar forms a gel on cooling to about 32º to 45º C that does not melt below 85º C. This hysteresis interval is a novel property of agar-agar that finds many uses in food applications. The gel strength of the agar-agar is influenced by concentration, time, pH, and sugar content. The pH noticeably affects the strength of the agar gel; as the pH decreases, the gel strength weakens. Sugar content also has a considerable effect over agar gel. Increasing levels of sugar make gels with harder but a less cohesive texture.

[0050] Following extensive studies Applicant determined not only were two specific gelling agents required, but it was necessary to control their relative amounts, and where formulations showed syneresis, the addition of a thickening agent, preferably xanthangum, in amounts of 0.1 to 0.4% was required to overcome the technical challenge of syneresis.

[0051] Other minor changes to the amounts of other ingredients present, and minor changes in pH also proved desirable.

[0052] The three gelling agents may broadly be used in the relative proportions (by weight) in a ratio, relative to the alginate, of from:ii) carrageenan greater than 1.0 to 6.2,iv) agar 0.2 to 2.1, andiii) alginate 1.0with the proviso that the carrageenan is present in the greatest amount.

[0053] The three gelling agents are optimally used in the relative proportions (by weight) in a ratio, relative to the alginate, of from:ii) carrageenan - 1.6 to 4.8,iv) agar - 0.5 to 1.5, andiii) alginate - 1.0.with the proviso that the carrageenan is present in the greatest amount.

[0054] Broadly the carrageenan is present in an amount, by weight %, of from 0.13 to 0.53, the agar is present in an amount, by weight %, of from 0.02 to 0.18, and the alginate is present in an amount, by weight %, of from 0.05 to 0.16, and in some cases as much as 0.21, with the proviso that the carrageenan is present in the greatest amount.

[0055] The higher amounts of alginate are preferred when the water is increased relative to the agar and alginate, and a thickening agent is added, as for example in the 40 mL formulations illustrated.

[0056] More preferably still the carrageenan is present in an amount, by weight %, of from 0.20 to 0.41, the agar is present in an amount, by weight %, of from 0.06 to 0.13. and the alginate is present in an amount, by weight %, of from 0.05 to 0.16, and in some cases as much as 0.21 with the proviso that the carrageenan is present in the greatest amount.

[0057] The higher amounts of alginate are preferred when the water is increased relative to the agar and alginate, and a thickening agent is added, as for example in the 40 mL formulations illustrated.

[0058] The preferred carrageenan is kappa carrageenan, the preferred agar is agar-agar, and the preferred alginate is sodium alginate.

[0059] To facilitate gelling of the alginate the cation donator comprises a divalent cation which facilitates cross linking of the alginate.

[0060] Preferably thev) at least one divalent cation is a calcium or magnesium cation, offered as a salt.

[0061] In a preferred embodiment thev) cation donator is magnesium chloride.

[0062] The ratio of alginate (present and measured as the weight of the salt) to the divalent cation (present and measured as the weight of the salt) is from 1.5:1 to 6:1.

[0063] The amount, by weight %, of the divalent cation (present as the salt) is from 0.03 to 0.06.

[0064] When syneresis is observed, it may be desirable to decrease the lower level of the divalent cation (present as the salt) from 0.03% to 0.01%.

[0065] Preferably thevi) at least one preservative is selected from lactic acid, potassium sorbate, sorbic acid and sodium benzoate.

[0066] In a preferred embodiment the preservative is potassium sorbate.

[0067] Preferably thevii) at least one pH modifier is an acidifying agent, alkalizing agent (base) or buffering agent depending on the API. Exemplary modifiers include: acetic acid, citric acid, hydrochloric acid, malic acid, phosphoric acid and sodium bicarbonate, sodium citrate sodium hydroxide.

[0068] The pH is in general controlled to be between 4.0 and 7.5. The preferred pH is selected based on:• the reference to physiological function of the API,• the solubility of the API in aqueous solution and its form when encapsulated or carried in the gel, and• the pKa of the API.

[0069] It varies for the API with the favoured pH for the exemplary APIs being:• Cetirizine pH 4.2 to 5.2, preferably 4.7,• Ibuprofen pH 6.4 to 7.4, preferably 6.9, and• Metformin pH 4.5 to 5.5, preferably 5.0.

[0070] For embodiments where the water volume increases to make a 40 mL drinkable gel and a thickening agent added to address the syneresis resulting from higher water concentrations the pH may also be altered as follows:• Cetirizine pH 4.4 to 5.4, preferably 4.9,• Ibuprofen pH 6.5 to 7.5, pH 7.0, and• Metformin pH 4.3 to 5.3, preferably 4.8.

[0071] In some embodiments it is desirable to includeix) at least one sweetener.

[0072] A preferred sweetener is sucralose and / or sorbitol.

[0073] In some embodiments it is desirable to includex) an emulsifier.

[0074] A preferred emulsifier is lecithin.

[0075] In some embodiments it is desirable to includexi) an oil.

[0076] A preferred oil is sunflower oil.

[0077] In some embodiments it is desirable to includexii) a flavouring.

[0078] Flavouring can refer to sweet, salty, sour, bitter, umami, floral, herbal, woody, fresh, earthy or spice flavours.

[0079] Preferred flavourings include fruit flavours e.g. blood orange, grape or an essential oil (e.g. menthol).

[0080] In some embodiments, namely those with additional water as exemplified by the 40 mL embodiments, it is desirable to includexiii) a thickening agent, more particularly one which counters any residual syneresis that may occur using the specified gel combination.

[0081] A preferred thickening agent is xanthan gum, which may be incorporated in an amount by % of from 0.1 to 0.4% and replaces a corresponding amount of water.

[0082] The amount may differ depending on the API.

[0083] With respect to the weight percent figures, for “generic” claims these are based on the essential components specified and exclude optional excipients. However, for specific drug formulations they include all identified excipients.

[0084] The actual amounts vary with the particular API selected.

[0085] In a first embodiment the BCS Class I API is e.g. Cetirizine or a salt or solution thereof.

[0086] Preferably the salt is a hydrochloride.

[0087] An exemplary BCS Class I formulation is illustrated where the API is Cetirizine and comprises ingredients (by weight %) in the range as set out in Table 1a.Table 1aActive / Excipient Min % Max %viii) Water 65.00 to 100.00vii) pH Modifier(s) 0.08 0.50i) BCS Class I API - e.g.Cetirizine Dihydrochloride 0.02 0.06vi) Preservative 0.04 0.20v) Divalent Cation 0.02 0.06v) Monovalent Cation 0.01 0.03iv) Agar 0.06 0.20ii) Carrageenan 0.20 0.50iii) Sodium Alginate 0.09 0.20xii) Flavouring 0.06 0.20ix) Sweetener(s) 0.00 10.00

[0088] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 1b.Table 1bActive / Excipient Min % Max %viii) Water 64.01 to 100.00vii) Citric Acid 0.08 0.14vii) Sodium Citrate 0.22 0.41i) Cetirizine Dihydrochloride 0.03 0.05vi) Potassium Sorbate 0.06 0.12v) Magnesium Chloride 0.03 0.05v) Potassium Chloride 0.01 0.02iv) Agar Agar 0.07 0.12ii) Kappa Carrageenan 0.20 0.38iii) Sodium Alginate 0.09 0.16xii) Flavouring 0.06 0.12ix) Sucralose 0.01 0.02ix) Sorbitol 0.00 9.51

[0089] Most preferably still the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 1c and Table 1d has a pH of 4.7.Table 1cActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 98.67vii) Citric Acid 0.03 0.12vii) Sodium Citrate 0.09 0.34i) Cetirizine Dihydrochloride 0.01 0.04vi) Potassium Sorbate 0.03 0.10v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02iv) Agar Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.32iii) Sodium Alginate 0.03 0.14xii) Flavouring – Menthol 0.03 0.10ix) Sucralose 0.01 0.02Total 25.34 100.00Table 1dActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 91.45vii) Citric Acid 0.03 0.11vii) Sodium Citrate 0.09 0.32i) Cetirizine Dihydrochloride 0.01 0.04vi) Potassium Sorbate 0.03 0.09v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02iv) Agar Agar 0.03 0.09ii) Kappa Carrageenan 0.08 0.29iii) Sodium Alginate 0.03 0.13xii) Flavouring - BloodOrange or Grape 0.03 0.09ix) Sucralose 0.01 0.02ix) Sorbitol 2.00 7.32Total 27.34 100.00

[0090] In a second embodiment the BCS Class II API is Ibuprofen or a salt or solution thereof.

[0091] An exemplary BCS Class II formulation is illustrated where the API is Ibuprofen and comprises ingredients (by weight %) in the range as set out in Table 2a.Table 2aActive / Excipient Min % Max %viii) Water 65.00 to 100.00i) BCS Class II API - e.g.Ibuprofen Sodium 0.60 1.40vi) Preservative 0.01 0.20 v) Divalent Cation 0.02 0.07v) Monovalent Cation 0.01 0.04vii) pH Modifier(s) 0.05 0.70iv) Agar 0.05 0.20ii) Carrageenan 0.10 0.45iii) Alginate 0.04 0.20

[0092] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 2b.Table 2bActive / Excipient Min % Max %viii) Water 68.44 to 100.00i) Ibuprofen Sodium 0.70 1.30vi) Potassium Sorbate 0.07 0.13v) Magnesium Chloride 0.03 0.06v) Potassium Chloride 0.01 0.03vii) Sodium Bicarbonate 0.34 0.64vii) Citric Acid 0.06 0.11iv) Agar Agar 0.07 0.13ii) Kappa Carrageenan 0.22 0.41iii) Sodium Alginate 0.06 0.11

[0093] Most preferably still the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 2c and has a pH of 6.9.Table 2cActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 97.77i) Ibuprofen Sodium 0.26 1.00vi) Potassium Sorbate 0.03 0.10v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02vii) Sodium Bicarbonate 0.13 0.49vii) Citric Acid 0.02 0.08iv) Agar Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.31iii) Sodium Alginate 0.02 0.08Total 25.57 100.00

[0094] In a third embodiment the BCS Class III API is Metformin, and the formulation comprises ingredients (by weight %) in the range as set out in Table 3a.Table 3a _| Active / Excipient | Min % | Max %viii) Water 55.00 to 100.00 vi) Preservative 0.05 0.15v) Divalent Cation 0.02 0.06v) Monovalent Cation 0.01 0.03vii) pH Modifier 0.04 0.40iv) Agar 0.04 0.40ii) Carrageenan 0.15 1.20iii) Alginate 0.04 0.35ix) Sweetener 0.00 10.00xi) Oil 0.05 4.00x) Emulsifier 0.20 0.60i) BCS Class III API - e.g.Metformin Hydrochloride 0.03 4.00xii) Flavouring 0.10 0.85

[0095] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 3b.Table 3bActive / Excipient Min % Max %viii) Water 62.63 to 100.00vi) Potassium Sorbate 0.06 0.12v) Magnesium Chloride 0.03 0.05v) Potassium Chloride 0.01 0.02vii) Citric Acid 0.05 0.10iv) Agar Agar 0.06 0.12ii) Kappa Carrageenan 0.20 0.37iii) Sodium Alginate 0.05 0.10ix) Sweetener 0.00 9.30xi) Sunflower Oil 0.25 0.47x) Lecithin 0.25 0.47i) Metformin Hydrochloride 1.25 2.33xii) Flavouring 0.13 0.23ix) Sucralose 0.01 0.02

[0096] Most preferably still the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 3c and Table 3d and has a pH of 5.0.Table 3cActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 94.54vi) Potassium Sorbate 0.03 0.09v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02vii) Citric Acid 0.02 0.08iv) Agar Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.30iii) Sodium Alginate 0.02 0.08xi) Sunflower Oil 0.10 0.38x) Lecithin 0.10 0.38i) Metformin Hydrochloride 1.00 3.78xii) Flavouring – Menthol 0.05 0.19ix) Sucralose 0.01 0.02Total 26.44 100.00Table 3dActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 87.89vi) Potassium Sorbate 0.03 0.09v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02vii) Citric Acid 0.02 0.07iv) Agar Agar 0.03 0.09ii) Kappa Carrageenan 0.08 0.28iii) Sodium Alginate 0.02 0.08ix) Sorbitol 2.00 7.03xi) Sunflower Oil 0.10 0.35x) Lecithin 0.10 0.35i) Metformin Hydrochloride 1.00 3.52xii) Flavouring - BloodOrange or Grape 0.05 0.18ix) Sucralose 0.01 0.02Total 28.44 100.00

[0097] Where the amount of the three gelling agents remains as per the embodiments above, but the volume of water is increased to provide a drinkable gel of 40 mL, the amounts of ingredients may be replaced as set out in Tables 8a, 8b, 8c and 8d (for BCS Class I formulations), Tables 9a, 9b, 9c and 9d (for BCS Class II formulations) and Tables 10a, 10b, 10c and 10d (for BCS Class III formulations).Table 8aActive / Excipient Min % Max %Water 49.92 to 100.00pH Modifier(s) 0.06 0.71BCS Class I API – e.g. 0.01 3.25Cetirizine DihydrochloridePreservative 0.05 0.15Divalent Cation 0.02 0.06Monovalent Cation 0.01 0.04Agar 0.05 0.15Carrageenan 0.16 0.49Alginate 0.07 0.21Flavouring 0.01 2.60Sweetener(s) 0.01 12.00 Thickening Agent 0.10 0.40Table 8bActive / Excipient Min % Max %Water 71.31 to 100.00 Citric Acid 0.09 0.14 Sodium Citrate 0.26 0.40 Cetirizine Dihydrochloride 0.02 2.50 Potassium Sorbate 0.07 0.12 Magnesium Chloride 0.03 0.05 Potassium Chloride 0.01 0.03 Agar Agar 0.07 0.12 Kappa Carrageenan 0.23 0.38 Sodium Alginate 0.11 0.16 Flavouring 0.01 2.00 Sucralose 0.01 0.03 Sorbitol 0.00 8.78 Xanthan Gum 0.10 0.40Table 8cActive / Excipient Mass (g) Percentage (%) Water 39.329 98.32 Citric Acid 0.047 0.12 Sodium Citrate 0.135 0.34 Cetirizine Dihydrochloride 0.010 0.03 Potassium Sorbate 0.038 0.10 Magnesium Chloride 0.015 0.04 Potassium Chloride 0.006 0.02 Agar Agar 0.040 0.10 Kappa Carrageenan 0.127 0.32 Sodium Alginate 0.055 0.14 Flavouring - Menthol 0.070 0.18 Sucralose 0.008 0.02 Xanthan Gum 0.120 0.30Total 40.000 100.00Table 8dActive / Excipient Mass (g) Percentage (%) Water 36.427 91.07Citric Acid 0.045 0.11 Sodium Citrate 0.129 0.32 Cetirizine Dihydrochloride 0.010 0.03 Potassium Sorbate 0.037 0.09 Magnesium Chloride 0.015 0.04 Potassium Chloride 0.006 0.02 Agar Agar 0.037 0.09 Kappa Carrageenan 0.117 0.29 Sodium Alginate 0.053 0.13 Flavouring - Blood Orange or 0.070 0.18 GrapeSucralose 0.008 0.02 Sorbitol 2.926 7.32 Xanthan Gum 0.120 0.30Total 40.000 100.00Table 9aActive / Excipient Min % Max % Water 49.47 to 100.00 BCS Class II API - e.g. 0.36 1.95 Ibuprofen SodiumPreservative 0.06 0.16 Divalent Cation 0.02 0.06 Monovalent Cation 0.01 0.04 pH Modifier(s) 0.08 1.00 Agar 0.06 0.16 Carrageenan 0.18 0.49 Alginate 0.04 0.12 Flavouring 0.01 2.60 Sweetener(s) 0.00 12.00 Thickening Agent 0.10 0.40Table 9bActive / Excipient Min % Max %Water 70.67 to 100.00 Ibuprofen Sodium 0.51 1.50 Potassium Sorbate 0.08 0.12 Magnesium Chloride 0.03 0.05 Potassium Chloride 0.01 0.03 Sodium Bicarbonate 0.39 0.59 Citric Acid 0.12 0.18 Agar Agar 0.08 0.12Kappa Carrageenan 0.25 0.38 Sodium Alginate 0.06 0.09 Flavouring 0.01 2.00 Sucralose 0.01 0.03 Sorbitol 0.00 8.79 Xanthan Gum 0.10 0.40Table 9cActive / Excipient Mass (g) Percentage (%) Water 39.033 97.58 Ibuprofen Sodium 0.256 0.64 Potassium Sorbate 0.040 0.10 Magnesium Chloride 0.015 0.04 Potassium Chloride 0.008 0.02 Sodium Bicarbonate 0.195 0.49 Citric Acid 0.06 0.15 Agar Agar 0.040 0.10 Kappa Carrageenan 0.125 0.31 Sodium Alginate 0.030 0.08 Flavouring - Menthol 0.072 0.18 Sucralose 0.006 0.02 Xanthan Gum 0.120 0.30Total 40.000 100.00Table 9dActive / Excipient Mass (g) Percentage (%) Water 36.104 90.26 Ibuprofen Sodium 0.256 0.64 Potassium Sorbate 0.040 0.10 Magnesium Chloride 0.015 0.04 Potassium Chloride 0.008 0.02 Sodium Bicarbonate 0.195 0.49 Citric Acid 0.06 0.15 Agar Agar 0.040 0.10 Kappa Carrageenan 0.125 0.31 Sodium Alginate 0.030 0.08 Flavouring - Blood Orange or 0.072 0.18 GrapeSucralose 0.006 0.02 Sorbitol 2.929 7.32 Xanthan Gum 0.120 0.30Total 40.000 100.00Table 10aActive / Excipient Min % Max %Water 48.56 to 100.00 Preservative 0.05 0.14 Divalent Cation 0.01 0.05 Monovalent Cation 0.01 0.04 pH Modifier(s) 0.03 0.85 Agar 0.05 0.14 Carrageenan 0.16 0.44 Alginate 0.04 0.12 Sweetener(s) 0.00 12.00 Oil 0.20 0.55 Emulsifier 0.20 0.55 BCS Class III API -e.g. 0.70 3.90 Metformin HydrochlorideFlavouring 0.01 2.60 Thickening Agent 0.10 0.40Table 10bActive / Excipient Min % Max %Water 69.37 to 100.00 Potassium Sorbate 0.07 0.11 Magnesium Chloride 0.02 0.04 Potassium Chloride 0.01 0.03 Citric Acid 0.04 0.06 Agar Agar 0.07 0.11 Kappa Carrageenan 0.23 0.34 Sodium Alginate 0.06 0.09 Sorbitol 0.00 8.43 Sunflower Oil 0.28 0.42 Lecithin 0.28 0.42 Metformin Hydrochloride 1.00 3.00 Flavouring 0.01 2.00 Sucralose 0.01 0.03 Xanthan Gum 0.10 0.40Table 10cActive / Excipient Mass (g) Percentage (%) Water 38.237 95.59Potassium Sorbate 0.035 0.09Magnesium Chloride 0.014 0.04Potassium Chloride 0.006 0.02Citric Acid 0.020 0.05Agar Agar 0.038 0.10Kappa Carrageenan 0.118 0.30Sodium Alginate 0.030 0.08Sunflower Oil 0.150 0.38Lecithin 0.150 0.38Metformin Hydrochloride 1.000 2.50Flavouring - Menthol 0.074 0.19Sucralose 0.008 0.02Xanthan Gum 0.120 0.30Total 40.000 100.00Table 10dActive / Excipient Mass (g) Percentage (%)Water 35.453 88.63Potassium Sorbate 0.035 0.09Magnesium Chloride 0.014 0.04Potassium Chloride 0.006 0.02Citric Acid 0.020 0.05Agar Ahar 0.037 0.09Kappa Carrageenan 0.113 0.28Sodium Alginate 0.030 0.08Sorbitol 2.810 7.03Sunflower Oil 0.141 0.35Lecithin 0.141 0.35Metformin Hydrochloride 1.000 2.50Flavouring – Blood Orange or 0.072 0.18GrapeSucralose 0.008 0.02Xanthan Gum 0.120 0.30Total 40.000 100.00

[0098] The invention is further described, by way of example only, with reference to the drawing, Examples and detailed description given below.BRIEF DESCRIPTION OF THE DRAWINGS

[0099] Embodiments of the invention are further described hereinafter with reference to the accompanying drawing, in which:Fig 1 is a diagram illustrating the Biopharmaceutical Classification System (BCS).DETAILED DESCRIPTION

[0100] In developing a generic formulation for BCS Class I, II and III APIs, Applicant undertook a series of experiments and overcame a number of technical challenges.

[0101] For ease of following, set out below are a series of Examples, for an exemplary BCS Class I, II and III drug, followed by some comparative Examples which highlight some of the technical challenges overcome.

[0102] Each of the Examples was prepared using the methodology set out below:Method

[0103] Add the API (e.g. Cetirizine, Ibuprofen or Metformin), magnesium chloride, potassium chloride, and potassium sorbate to a beaker. Where applicable, add sweeteners sucralose and sorbitol. Add water and mix until dissolved. Measure the pH of the solution and pH adjust using citric acid, sodium citrate and / or sodium bicarbonate, where required. Using a stirring hot plate, heat the solution to 95°C to 100°C. Once the temperature has reached 95°C or above, slowly add the gelling agents (e.g. kappa carrageenan, agar and sodium alginate) and where applicable, add thickening agent xanthan gum and mix until completely dissolved. Finally, add any flavouring and mix until dissolved. Hot fill the gel into the pouch and cap immediately. Let cool to room temperature. Pouches may require air to inflate the pouch prior to filling. Where an emulsion is required, see e.g. Metformin Example the water is split and the emulsion mixed with the other components. The pouch facilitates delivery of the dosage form, which is a drinkable gel which shears on sucking.EXAMPLE 1

[0104] The drug Cetirizine was formulated, and the gelling agents were found to provide a satisfactory product when the ingredients were present in amounts (weight %) as illustrated in Table 1a below:Table 1aActive / Excipient Min % Max %viii) Water 65.00 to 100.00vii) pH modifier(s) 0.08 0.50i) BCS Class I API - e.g.Cetirizine Dihydrochloride 0.02 0.06vi) Preservative 0.04 0.20v) Divalent Cation 0.02 0.06v) Monovalent Cation 0.01 0.03iv) Agar 0.06 0.20ii) Carrageenan 0.20 0.50iii) Sodium Alginate 0.09 0.20xii) Flavouring 0.06 0.20ix) Sweetener(s) 0.00 10.00

[0105] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 1b below:Table 1bActive / Excipient Min % Max %viii) Water 64.01 to 100.00vii) Citric Acid 0.08 0.14vii) Sodium Citrate 0.22 0.41i) Cetirizine Dihydrochloride 0.03 0.05vi) Potassium Sorbate 0.06 0.12v) Magnesium Chloride 0.03 0.05v) Potassium Chloride 0.01 0.02iv) Agar Agar 0.07 0.12ii) Kappa Carrageenan 0.20 0.38iii) Sodium Alginate 0.09 0.16xii) Flavouring 0.06 0.12ix) Sucralose 0.01 0.02ix) Sorbitol 0.00 9.51

[0106] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 1c and 1d below with a pH of 4.7.Table 1cActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 98.67vii) Citric Acid 0.03 0.12vii) Sodium Citrate 0.09 0.34i) Cetirizine Dihydrochloride 0.01 0.04vi) Potassium Sorbate 0.03 0.10v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02iv) Agar Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.32iii) Sodium Alginate 0.03 0.14xii) Flavouring – Menthol 0.03 0.10ix) Sucralose 0.01 0.02Total 25.34 100.00Table 1dActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 91.45vii) Citric Acid 0.03 0.11vii) Sodium Citrate 0.09 0.32i) Cetirizine Dihydrochloride 0.01 0.04vi) Potassium Sorbate 0.03 0.09v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02iv) Agar Agar 0.03 0.09ii) Kappa Carrageenan 0.08 0.29iii) Sodium Alginate 0.03 0.13xii) Flavouring - BloodOrange or Grape 0.03 0.09ix) Sucralose 0.01 0.02ix) Sorbitol 2.00 7.32Total 27.34 100.00EXAMPLE 2

[0107] The drug Ibuprofen was formulated, and the gelling agents were found to provide a satisfactory product when the ingredients were present in amounts (weight %) as illustrated in Table 2a below:Table 2aActive / Excipient Min % Max %viii) Water 65.00 to 100.00i) BCS Class II API - e.g.Ibuprofen Sodium 0.60 1.40vi) Preservative 0.01 0.20v) Divalent Cation 0.02 0.07v) Monovalent Cation 0.01 0.04vii) pH modifier(s) 0.05 0.70iv) Agar 0.05 0.20ii) Carrageenan 0.10 0.45iii) Alginate 0.04 0.20

[0108] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 2b below:Table 2bActive / Excipient Min % Max %viii) Water 68.44 to 100.00i) Ibuprofen Sodium 0.70 1.30vi) Potassium sorbate 0.07 0.13v) Magnesium chloride 0.03 0.06v) Potassium chloride 0.01 0.03vii) Sodium bicarbonate 0.34 0.64vii) Citric acid 0.06 0.11iv) Agar Agar 0.07 0.13ii) Kappa Carrageenan 0.22 0.41iii) Sodium alginate 0.06 0.11

[0109] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 2c below with a pH of 6.9:Table 2cActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 97.77i) Ibuprofen Sodium 0.26 1.00vi) Potassium sorbate 0.03 0.10v) Magnesium chloride 0.01 0.04v) Potassium chloride 0.01 0.02vii) Sodium bicarbonate 0.13 0.49vii) Citric acid 0.02 0.08iv) Agar Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.31iii) Sodium alginate 0.02 0.08Total 25.57 100.00EXAMPLE 3

[0110] The drug Metformin was formulated, and the gelling agents were found to provide a satisfactory product when the ingredients were present in amounts (weight %) as illustrated in Table 3a below:Table 3aActive / Excipient Min % Max %viii) Water 55.00 to 100.00vi) Preservative 0.05 0.15v) Divalent cation 0.02 0.06v) Monovalent cation 0.01 0.03vii) pH modifier 0.04 0.40iv) Agar 0.04 0.40ii) Carrageenan 0.15 1.20iii) Alginate 0.04 0.35ix) Sweetener 0.00 10.00xi) Oil 0.05 4.00x) Emulsifier 0.20 0.60i) Metformin hydrochloride 0.03 4.00xii) Flavouring 0.10 0.85

[0111] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 3b below:Table 3bActive / Excipient Min % Max %viii) Water 62.63 to 100.00vi) Potassium sorbate 0.06 0.12v) Magnesium chloride 0.03 0.05v) Potassium chloride 0.01 0.02vii) Citric acid 0.05 0.10iv) Agar Agar 0.06 0.12ii) Kappa Carrageenan 0.20 0.37iii) Sodium alginate 0.05 0.10ix) Sweetener 0.00 9.30xi) Sunflower Oil 0.25 0.47x) Lecithin 0.25 0.47i) Metformin hydrochloride 1.25 2.33xii) Flavouring 0.13 0.23ix) Sucralose 0.01 0.02

[0112] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 3c and 3d below with a pH of 5.0:Table 3cActive / Excipient Mass (g) Percentage (%)viii) Water 25.00 94.54vi) Potassium sorbate 0.03 0.09v) Magnesium chloride 0.01 0.04v) Potassium chloride 0.01 0.02vii) Citric acid 0.02 0.08iv) Agar Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.30iii) Sodium alginate 0.02 0.08xi) Sunflower Oil 0.10 0.38x) Lecithin 0.10 0.38i) Metformin hydrochloride 1.00 3.78xii) Flavouring – Menthol 0.05 0.19ix) Sucralose 0.01 0.02Total 26.44 100.00Table 3d _ _ _I Active / Excipient | Mass (g) | Percentage (%) |viii) Water 25.00 87.89 vi) Potassium sorbate 0.03 0.09v) Magnesium chloride 0.01 0.04v) Potassium chloride 0.01 0.02vii) Citric acid 0.02 0.07iv) Agar Agar 0.03 0.09ii) Kappa Carrageenan 0.08 0.28iii) Sodium alginate 0.02 0.08ix) Sorbitol 2.00 7.03xi) Sunflower Oil 0.10 0.35x) Lecithin 0.10 0.35i) Metformin hydrochloride 1.00 3.52xii) Flavouring - BloodOrange or Grape 0.05 0.18ix) Sucralose 0.01 0.02Total 28.44 100.00DEVELOPMENT AND COMPARATIVE EXAMPLESExperimental series 1 (BCS class II)

[0113] The ibuprofen gel created in PCT / IB2024 / 054921 had a firm texture and Applicant desired a thinner more drinkable texture.

[0114] Starting from this Ibuprofen formulation, Table 4a, they sought to develop a thinner more drinkable gel.Table 4aIbuprofen gel (200 mg / 25ml) – pH 6.8Active / Excipient Mass Unit %i) Ibuprofen 0.20 g 0.78viii) Water 25.00 g 97.42vi) Potassium sorbate 0.03 g 0.10v) Magnesium chloride 0.11 g 0.43v) Potassium chloride 0.01 g 0.02iv) Agar 0.15 g 0.58ii) Kappa carrageenan 0.10 g 0.39iii) Sodium alginate 0.05 g 0.19vii) Citric acid 0.02 g 0.08TOTAL 25.66 g 100.00

[0115] To this end they reduced the original gelling agents: agar, kappa and alginate in the masses 0.15g, 0.10g and 0.05g by (1a) 10%, (1b) 20% and (1c) 25% to observe texture changes - see Table 4b.Table 4b(1a) 10% Reduction (1 b) 20% Reduction (1 c) 25% Reduction Active / Mass (g) Percentage Mass (g) Percentage Mass Percentage Excipient (%) (%) (g) (%) ibuprofen 0.26 1.00 0.26 1.00 0.26 1.00 sodiumWater 25.00 97.70 25.00 97.77 25.00 97.87 Potassium 0.03 0.10 0.03 0.10 0.03 0.10 sorbateMagnesium 0.01 0.04 0.01 0.04 0.01 0.04 chloridePotassium 0.01 0.02 0.01 0.02 0.01 0.02 chlorideAgar 0.14 0.53 0.13 0.50 0.11 0.44 Kappa 0.09 0.35 0.08 0.31 0.08 0.29 carrageenanSodium alginate 0.05 0.18 0.04 0.17 0.04 0.15 Citric acid 0.02 0.08 0.02 0.08 0.02 0.08

[0116] Gel 1a was still quite firm, gel 1b was semi-firm and gel 1c was soft. Gel 1b – Table 4c was selected for further development.

[0117] Applicant tested 75%, 50% and 25% of the original gelling agents: agar, kappa carrageenan and sodium alginate. The 75% and 50% gel had a firm texture but released water (syneresis) over time, with the 50% gel releasing most. The 25% gel had not set and was too watery. This demonstrated that the reduction of gelling agents was too extreme resulting in the collapsing of the gel - see Table 4c.Table 4cActive / Excipient Min % Max %Ibuprofen sodium 1.00 1.01Water 98.02 98.50Potassium sorbate 0.10 0.10Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.13 0.38Kappa carrageenan 0.08 0.24Sodium alginate 0.04 0.13Citric acid 0.08 0.08

[0118] Gel strength was investigated by increasing the agar concentration relative to the kappa carrageenan and sodium alginate, which were kept constant. The agar concentration was increased by 20%, 40%, 60% and 80% as illustrated in Table 4d. Table 4dActive / Excipient Min % Max %Ibuprofen sodium 1.01 1.01Water 98.31 98.46Potassium sorbate 0.10 0.10Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.05 0.20Kappa carrageenan 0.16 0.16Sodium alginate 0.08 0.08Citric acid 0.08 0.08

[0119] The gel with 40% agar was firm yet soft when mechanically crushed. It had a good texture and was further investigated.

[0120] Applicant then investigated potentially making the Carrageenan the primary gelling agent, with agar the secondary gelling agent - see formulations of Table 4e. Table 4eActive / Excipient Min % Max %Ibuprofen sodium 1.01 1.01Water 98.15 98.30Potassium sorbate 0.10 0.10Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.05 0.20Kappa carrageenan 0.31 0.31Sodium alginate 0.08 0.08Citric acid 0.08 0.08

[0121] By doubling the concentration of kappa carrageenan, they obtained a much-improved gel texture. However, pH and flavouring remained a challenge and so sodium bicarbonate was added resulting in a favoured composition - See Table 2c.Experimental series 2 (BCS class I)

[0122] Applicant utilised a base gel based on Ibuprofen gel (Table 2c) for Cetirizine as set out in Table 5a.Table 5aActive / Excipient Mass (g) Percentage (%)i) Cetirizine Dihydrochloride 0.01 0.04viii) Water 25.00 99.21vi) Potassium Sorbate 0.03 0.10v) Magnesium Chloride 0.01 0.04v) Potassium Chloride 0.01 0.02iv) Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.32iii) Sodium Alginate 0.02 0.09vii) Citric Acid 0.02 0.08

[0123] As the pH of the gel was less than 4.0, and the preferred pH range is between 4.0 - 6.0, Applicant looked first to modify the pH.

[0124] They investigated both (i) changing the acid source, and (ii) introducing a buffer.

[0125] A change of acid is illustrated in Table 5bTable 5bActive / Excipient Min % Max %Cetirizine Dihydrochloride 0.04 0.04Water 99.14 99.23Potassium Sorbate 0.10 0.10Magnesium Chloride 0.04 0.04Potassium Chloride 0.02 0.02Agar 0.10 0.10Kappa Carrageenan 0.32 0.32Sodium Alginate 0.09 0.09Malic Acid 0.10 0.20

[0126] The malic acid tested at ranges 0.1% - 0.2% yielded the same result as citric acid.

[0127] Introducing a buffer (sodium citrate) - also considered a pH control agent proved largely effective at modifying the pH to between 4.5 and 5, but some syneresis was evident with the change in pH - Table 5c.Table 5cActive / Excipient Mass (g) Percentage (%)Cetirizine Dihydrochloride 0.01 0.04Water 25.00 98.83Potassium Sorbate 0.03 0.10Magnesium Chloride 0.01 0.04Potassium Chloride 0.01 0.02Agar 0.03 0.10Kappa Carrageenan 0.08 0.32Sodium Alginate 0.02 0.08Citric Acid 0.03 0.12Sodium Citrate 0.09 0.34

[0128] To address the syneresis of the gel Applicant adjusted the concentration of sodium alginate. They found, unlike for the case of Ibuprofen, where agar was in a slightexcess to alginate, the reverse was true - see Table 5d. However, carrageenan remained the primary gelling agent.Table 5dActive / Excipient Min % Max %Cetirizine Dihydrochloride 0.04 0.04Water 98.75 98.82Potassium sorbate 0.10 0.10Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.10 0.10Kappa Carrageenan 0.32 0.32Sodium alginate 0.10 0.17Citric acid 0.12 0.12Sodium citrate 0.34 0.34

[0129] They also determined it was desirable to add a sweetener and flavouring as illustrated in Table 5e.Table 5eActive / Excipient Min % Max %Cetirizine Dihydrochloride 0.04 0.04Water 98.57 98.67Potassium sorbate 0.10 0.10Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.10 0.10Kappa Carrageenan 0.32 0.32Sodium alginate 0.14 0.14Citric acid 0.12 0.12Sodium citrate 0.34 0.34Sucralose 0.02 0.02Flavouring 0.10 0.20

[0130] Different flavourings tried demonstrated that different flavourings could be used.

[0131] Flavouring was finalised for the Cetirizine gel with three flavours: (i) blood orange, (ii) grape and (iii) menthol. The Cetirizine gel with menthol was too sweet with sorbitol so it was removed – See Table 1c. Sorbitol was kept with the blood orange and grape flavours - See Table 1d.Experimental series 3 (BCS class III)

[0132] Applicant explored a single gelling agent with a first exemplary class III API (Metformin).

[0133] Metformin was tested with two of their gel basesa) agar and gellan gum - Table 6a, andb) agar, kappa carrageenan and sodium alginate - Table 6b.Table 6aActive / Excipient Mass (g) Percentage (%)Metformin Hydrochloride 1.00 3.12Water 25.00 77.89Potassium sorbate 0.08 0.23Agar 0.01 0.02Gellan gum 0.15 0.47Citric acid 0.05 0.14Sodium citrate 0.25 0.78Glycerol 5.57 17.35Table 6bActive / Excipient Mass (g) Percentage (%)i) Metformin Hydrochloride 1.00 3.82vii) Water 25.00 95.46vi) Potassium sorbate 0.03 0.10v) Magnesium chloride 0.01 0.04v) Potassium chloride 0.01 0.02iv) Agar 0.03 0.10ii) Kappa Carrageenan 0.08 0.31iii) Sodium alginate 0.02 0.080.02v) Citric acid 0.08

[0134] The texture of metformin was ideal in using gel base in Table 6b as the appearance of the gel was clear, had no undissolved particulates, was bitter but not stinging in the mouth.

[0135] In comparison to the gel in Table 6a, the gel was translucent, had undissolved particulates, was bitter and salty. The texture was not ideal in appearance nor taste.

[0136] Accordingly, Applicant continued the development of metformin with the kappa carrageenan, alginate and agar base formulation - Table 6b.

[0137] Due to the bitterness of metformin, Applicant explored the use of emulsions.

[0138] Emulsions are created by combining an emulsifier, oil and water. The emulsifier and oil selected were lecithin and sunflower oil respectively.

[0139] The concentrations of sunflower oil were tested between 0.08% and 1.87% - See Table 6c.Table 6cActive / Excipient Min % Max %Metformin Hydrochloride 3.80 3.73Water 57.01 55.99Potassium sorbate 0.10 0.09Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.10 0.10Kappa Carrageenan 0.30 0.30Sodium alginate 0.08 0.08Citric acid 0.08 0.08Water (emulsion) 38.01 37.33Lecithin 0.38 0.37Sunflower Oil 0.08 1.87

[0140] Higher concentrations of oil were more helpful in reducing the bitterness. Different concentrations of lecithin were tested to determine the ideal ratio between emulsifier and oil - Table 6d.Table 6dActive / Excipient Min % Max %Metformin Hydrochloride 3.80 3.73Water 57.01 55.89Potassium sorbate 0.10 0.09Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.10 0.10Kappa Carrageenan 0.30 0.30Sodium alginate 0.08 0.08Citric acid 0.08 0.08Water (emulsion) 38.01 37.26Lecithin 0.38 0.56Sunflower Oil0.08 1.86

[0141] The following formulation - Table 6e was most effective in reducing the bitter taste.Table 6eActive / Excipient Mass (g) Percentage (%)Metformin Hydrochloride 1.00 3.79Water 15.00 56.84Potassium sorbate0.03 0.09Magnesium chloride 0.01 0.04Potassium chloride 0.01 0.02Agar 0.03 0.10Kappa Carrageenan 0.08 0.30Sodium alginate 0.02 0.08Citric acid 0.02 0.08Water (emulsion) 10.00 37.89Lecithin 0.10 0.38Sunflower Oil0.10 0.38

[0142] As with Cetirizine dihydrochloride, Applicant was able to adjust sweetness (Table 6f) and flavouring (Table 6g). The sweetener used was sucralose and flavourings tested included the fruit flavours: strawberry, berry, watermelon, apple, cherry, grape, raspberry and blood orange and menthol.Table 6fActive / Excipient Min % Max %Metformin Hydrochloride 3.79 3.79Water 56.84 56.84Potassium sorbate 0.09 0.09Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.10 0.10Kappa Carrageenan 0.30 0.30Sodium alginate 0.08 0.08Citric acid 0.08 0.08Water (emulsion) 37.89 37.89Lecithin 0.38 0.38Sunflower Oil 0.38 0.38Sucralose 0.02 0.04Table 6gActive / Excipient Min % Max %Metformin Hydrochloride 2.74 2.74Water 68.43 68.60Potassium sorbate 0.07 0.07Magnesium chloride 0.03 0.03Potassium chloride 0.01 0.01Agar 0.07 0.07Kappa Carrageenan 0.22 0.22Sodium alginate 0.06 0.06Citric acid 0.06 0.06Water (emulsion) 27.37 27.44Lecithin 0.27 0.27Sunflower Oil 0.27 0.27Sucralose 0.01 0.03Flavouring 0.14 0.36

[0143] Sucralose was found to have quite an intense sweetness, and a more balanced sweetness was obtained using a combination of sucralose with sorbitol - Table 6h.Table 6hActive / Excipient Min % Max %Metformin Hydrochloride 3.45 3.71Water 51.82 55.67Potassium sorbate 0.09 0.09Magnesium chloride 0.04 0.04Potassium chloride 0.02 0.02Agar 0.09 0.10Kappa Carrageenan 0.28 0.30Sodium alginate 0.07 0.08Citric acid 0.07 0.08Water (emulsion) 34.55 37.11Lecithin 0.35 0.37Sunflower Oil 0.35 0.37Sucralose 0.02 0.02Flavouring 0.17 0.19Sorbitol 1.86 8.64

[0144] Preferred formulations for metformin are illustrated in Tables 3c and 3d respectively.Experimental series 4 (Larger drinkable volume and thickening agent)

[0145] In the previous experimental series, the total product volume was between 25 to 30 mL (or g), as exemplified for Cetirizine in Tables 1c and 1 d, Ibuprofen in Table 2c, and Metformin in Tables 3c and 3d.

[0146] Applicant desired to increase the product size to 40 mL (or g).

[0147] To achieve this, Applicant increased the water volume whilst keeping the other active / excipients at the same concentrations.

[0148] It was observed that syneresis occurred in a Cetirizine prototype, with a pH of 4.9, as illustrated in Table 7a below.Table 7aActive / Excipient Mass (g) Percentage (%)Water 36.547 91.37Citric Acid 0.045 0.11Sodium Citrate 0.129 0.32Cetirizine Dihydrochloride 0.010 0.03Potassium Sorbate 0.037 0.09Magnesium Chloride 0.015 0.04Potassium Chloride 0.006 0.02Agar Agar 0.037 0.09Kappa Carrageenan 0.117 0.29Sodium Alginate 0.053 0.13Flavouring – Blood 0.070 0.18Orange or GrapeSucralose 0.008 0.02Sorbitol 2.926 7.32Total 40.000 100.00 HEIGHT="263" WIDTH="344" SRC="imgf000034_0001_table.tif" / >

[0149] Accordingly, Applicant undertook some experiments to determine whether the addition of a thickening agent would address the syneresis. They selected xanthan gum and added it at different concentrations.

[0150] Xanthan gum is a high molecular weight polysaccharide produced by Xanthomonas campestris through microbial fermentation. It is widely used in pharmaceutical applications as a hydrophilic polymer and rheology modifier in various dosage forms including oral liquids, suspensions, topical gels and controlled release products. Its primary function includes thickening, stabilising and controlling drug release.

[0151] Xanthan gum has a cellulose-like backbone composed of p-(1-4)-D-glucose units with repeating trisaccharide side chains consisting of mannose-glucuronic acid-mannose, attached to alternate glucose residues. Some mannose units are acetylated while others are substituted with pyruvic acid residues. The carboxyl and pyruvate groups impart a negative charge contributing to the high-water solubility and electrostatic interactions with other excipients.

[0152] Upon contact with water, xanthan gum rapidly hydrates due to its numerous hydroxyl and carboxyl groups, forming a viscous pseudoplastic solution. The polymer chains expand and become entangled, creating a three-dimensional network that immobilises water molecules and increases viscosity. This network is responsible for the thickening effect.

[0153] The experiment in Table 7b incorporated xanthan gum at 0.01% as a thickening agent. The gel still exhibited syneresis.Table 7bActive / Excipient Mass (g) Percentage (%)Water 36.543 91.36Citric Acid 0.045 0.11Sodium Citrate 0.129 0.32Cetirizine Dihydrochloride 0.010 0.03Potassium Sorbate 0.037 0.09Magnesium Chloride 0.015 0.04Potassium Chloride 0.006 0.02Agar Agar 0.037 0.09Kappa Carrageenan 0.117 0.29Sodium Alginate 0.053 0.13Flavouring – Blood 0.070 0.18Orange or GrapeSucralose 0.008 0.02Sorbitol 2.926 7.32Xanthan Gum 0.004 0.01Total 40.000 100.00 HEIGHT="296" WIDTH="344" SRC="imgf000035_0001_table.tif" / >

[0154] Applicant therefore investigated varying amounts of xanthan gum as illustrated in Table 7c.Table 7cActive / Excipient Min % Max %Water 90.87 91.36Citric Acid 0.11 0.11Sodium Citrate 0.32 0.32Cetirizine Dihydrochloride 0.03 0.03Potassium Sorbate 0.09 0.09Magnesium Chloride 0.04 0.04Potassium Chloride 0.02 0.02Agar Agar 0.09 0.09Kappa Carrageenan 0.29 0.29Sodium Alginate 0.13 0.13Flavouring – Blood 0.18 0.18Orange or GrapeSucralose 0.02 0.02Sorbitol 7.32 7.32Xanthan Gum 0.01 0.50

[0155] The preferred gels were achieved when xanthan gum was present between 0.1% to 0.4%. Minimal syneresis was observed at these ranges. The gel at the highestconcentration of 0.5% reduced syneresis but was difficult to incorporate with the other excipients. The preferred concentration of xanthan gum was 0.3%.

[0156] Due to the addition of water and xanthan gum, it proved desirable to increase the flavouring to account for the higher product volume. Applicant found that flavouring between 0.01 % to 2.6% was acceptable depending on the final flavour selected. The preferred generic and specific ranges for e.g. a 40 mL (or g) product containing API are illustrated in Tables 8a and 8b below.Table 8aActive / Excipient Min % Max %Water 49.92 to 100.00pH modifier(s) 0.06 0.71BCS Class I API – e.g. 0.01 3.25Cetirizine DihydrochloridePreservative 0.05 0.15Divalent Cation 0.02 0.06Monovalent Cation 0.01 0.04Agar 0.05 0.15Carrageenan 0.16 0.49Alginate 0.07 0.21Flavouring 0.01 2.60Sweetener(s) 0.01 12.00Thickening Agent 0.10 0.40Table 8bActive / Excipient Min % Max %Water 71.31 to 100.00Citric Acid 0.09 0.14Sodium Citrate 0.26 0.40Cetirizine Dihydrochloride 0.02 2.50Potassium Sorbate 0.07 0.12Magnesium Chloride 0.03 0.05Potassium Chloride 0.01 0.03Agar Agar 0.07 0.12Kappa Carrageenan 0.23 0.38Sodium Alginate 0.11 0.16Flavouring 0.01 2.00Sucralose 0.01 0.03Sorbitol 0.00 8.78Xanthan Gum 0.10 0.40

[0157] Based on the above the Cetirizine Dihydrochloride gels of Tables 1c and 1d were reformulated as 40 mL (or g) drinkable gels, delivered via a pouch at a pH of 4.9 - Table 8c and Table 8d.Table 8cActive / Excipient Mass (g) Percentage (%)Water 39.329 98.32Citric Acid 0.047 0.12Sodium Citrate 0.135 0.34Cetirizine Dihydrochloride 0.010 0.03Potassium Sorbate 0.038 0.10Magnesium Chloride 0.015 0.04Potassium Chloride 0.006 0.02Agar Agar 0.040 0.10Kappa Carrageenan 0.127 0.32Sodium Alginate 0.055 0.14Flavouring – Menthol 0.070 0.18Sucralose 0.008 0.02Xanthan Gum 0.120 0.30Total 40.000 100.00 HEIGHT="285" WIDTH="351" SRC="imgf000037_0001_table.tif" / >Table 8dActive / Excipient Mass (g) Percentage (%)Water 36.427 91.07Citric Acid 0.045 0.11Sodium Citrate 0.129 0.32Cetirizine Dihydrochloride 0.010 0.03Potassium Sorbate 0.037 0.09Magnesium Chloride 0.015 0.04Potassium Chloride 0.006 0.02Agar Agar 0.037 0.09Kappa Carrageenan 0.117 0.29Sodium Alginate 0.053 0.13Flavouring – Blood Orange or 0.070 0.18GrapeSucralose 0.008 0.02Sorbitol 2.926 7.32Xanthan Gum 0.120 0.30Total 40.000 100.00 HEIGHT="296" WIDTH="354" SRC="imgf000037_0002_table.tif" / >

[0158] Based on the above the Ibuprofen gels of Tables 2a to 2c were reformulated as 40 mL (or g) drinkable gels - Tables 9a to 9d, delivered via a pouch at a pH of 7.0.Table 9aActive / Excipient Min % Max % Water 49.47 to 100.00 BCS Class II API –Ibuprofen 0.36 1.95 SodiumPreservative 0.06 0.16 Divalent Cation 0.02 0.06 Monovalent Cation 0.01 0.04 pH modifier(s) 0.08 1.00 Agar 0.06 0.16 Carrageenan 0.18 0.49 Alginate 0.04 0.12 Flavouring 0.01 2.60 Sweetener(s) 0.00 12.00 Thickening Agent 0.10 0.40Table 9bActive / Excipient Min % Max % Water 70.67 to 100.00 Ibuprofen Sodium 0.51 1.50 Potassium Sorbate 0.08 0.12 Magnesium Chloride 0.03 0.05 Potassium Chloride 0.01 0.03 Sodium Bicarbonate 0.39 0.59 Citric Acid 0.12 0.18 Agar Agar 0.08 0.12 Kappa Carrageenan 0.25 0.38 Sodium Alginate 0.06 0.09 Flavouring 0.01 2.00 Sucralose 0.01 0.03 Sorbitol 0.00 8.79 Xanthan Gum 0.10 0.40Table 9cActive / Excipient Mass (g) Percentage (%) Water 39.033 97.58 Ibuprofen Sodium 0.256 0.64 Potassium Sorbate 0.040 0.10 Magnesium Chloride 0.015 0.04 Potassium Chloride 0.008 0.02 Sodium Bicarbonate 0.195 0.49Citric Acid 0.06 0.15Agar Agar 0.040 0.10Kappa Carrageenan 0.125 0.31Sodium Alginate 0.030 0.08Flavouring – Menthol 0.072 0.18Sucralose 0.006 0.02Xanthan Gum 0.120 0.30Total 40.000 100.00 HEIGHT="144" WIDTH="352" SRC="imgf000039_0001_table.tif" / >Table 9dActive / Excipient Mass (g) Percentage (%)Water 36.104 90.26Ibuprofen Sodium 0.256 0.64Potassium Sorbate 0.040 0.10Magnesium Chloride 0.015 0.04Potassium Chloride 0.008 0.02Sodium Bicarbonate 0.195 0.49Citric Acid 0.06 0.15Agar Agar 0.040 0.10Kappa Carrageenan 0.125 0.31Sodium Alginate 0.030 0.08Flavouring – Blood Orange or 0.072 0.18GrapeSucralose 0.006 0.02Sorbitol 2.929 7.32Xanthan Gum 0.120 0.30Total 40.000 100.00

[0159] Based on the above the Metformin gels of Tables 3a to 3d were reformulated as 40 mL (or g) drinkable gels - Tables 10a to 10d, delivered via a pouch at a pH of 4.8.Table 10aActive / Excipient Min % Max %Water 48.56 to 100.00Preservative 0.05 0.14Divalent Cation 0.01 0.05Monovalent Cation 0.01 0.04pH modifier(s) 0.03 0.85Agar 0.05 0.14Carrageenan 0.16 0.44Alginate 0.04 0.12Sweetener(s) 0.00 12.00 Oil 0.20 0.55 Emulsifier 0.20 0.55 BCS Class III API -Metformin 0.70 3.90 HydrochlorideFlavouring 0.01 2.60 Thickening Agent 0.10 0.40Table 10bActive / Excipient Min % Max %Water 69.37 to 100.00 Potassium Sorbate 0.07 0.11 Magnesium Chloride 0.02 0.04 Potassium Chloride 0.01 0.03 Citric Acid 0.04 0.06 Agar Agar 0.07 0.11 Kappa Carrageenan 0.23 0.34 Sodium Alginate 0.06 0.09 Sorbitol 0.00 8.43 Sunflower Oil 0.28 0.42 Lecithin 0.28 0.42 Metformin Hydrochloride 1.00 3.00 Flavouring 0.01 2.00 Sucralose 0.01 0.03 Xanthan Gum 0.10 0.40Table 10cActive / Excipient Mass (g) Percentage (%) Water 38.237 95.59 Potassium Sorbate 0.035 0.09 Magnesium Chloride 0.014 0.04 Potassium Chloride 0.006 0.02 Citric Acid 0.020 0.05 Agar Agar 0.038 0.10 Kappa Carrageenan 0.118 0.30 Sodium Alginate 0.030 0.08 Sunflower Oil 0.150 0.38 Lecithin 0.150 0.38 Metformin Hydrochloride 1.000 2.50 Flavouring - Menthol 0.074 0.19 Sucralose 0.008 0.02 Xanthan Gum 0.120 0.30Total 40.000 100.00Table 10dActive / Excipient Mass (g) Percentage (%) Water 35.453 88.63 Potassium Sorbate 0.035 0.09 Magnesium Chloride 0.014 0.04 Potassium Chloride 0.006 0.02 Citric Acid 0.020 0.05 Agar Ahar 0.037 0.09 Kappa Carrageenan 0.113 0.28 Sodium Alginate 0.030 0.08 Sorbitol 2.810 7.03 Sunflower Oil 0.141 0.35 Lecithin 0.141 0.35 Metformin Hydrochloride 1.000 2.50 Flavouring - Blood Orange or 0.072 0.18 GrapeSucralose 0.008 0.02 Xanthan Gum 0.120 0.30Total 40.000 100.00

Claims

CLAIMS1. A textured gel formulation, capable of formulating Active Pharmaceutical Ingredients (APIs) spanning Biopharmaceutical Classification System (BCS) Class I, II and III, comprising:i) a Biopharmaceutical Classification System (BCS) Class I, II or III Active Pharmaceutical Ingredient (API), or a salt or solution thereof, ii) a primary gelling agent which is a carrageenan,iii) a first secondary gelling agent which is an alginate,iv) a second secondary gelling agent which is an agar,v) at least one cation donator,vi) a preservative,vii) at least one pH modifier, andviii) water.

2. A textured gel formulation as claimed in claim 1 which further comprises one or more of:ix) at least one sweetener,x) an emulsifier,xi) an oilxii) a flavouring, andxiii) a thickening agent.

3. A textured gel formulation as claimed in claim 1 wherein thev) at least one cation donator comprisesa. a divalent cation, and optionallyb. a monovalent cation.

4. A textured gel formulation as claimed in claim 3 whereina) the divalent cation is magnesium, andb) the monovalent cation is potassium.

5. A textured gel formulation as claimed in claim 3 or 4 wherein thev) cation donator is a chloride salt of the cation.

6. A textured gel formulation as claimed in claim 1 wherein thevi) preservative is potassium sorbate.

7. A textured gel formulation as claimed in claim 1 whereinvii) the at least one pH modifier is selected from citric acid, sodium citrate, and sodium bicarbonate.

8. A textured gel formulation as claimed in claim 7 wherein the pH is from pH 4.0 to 7.5.

9. A textured gel formulation as claimed in claim 1 whereiniii) the alginate is present in a greater amount by weight thaniv) the agar.with the proviso that the carrageenan is present in the greatest amount.

10. A textured gel formulation as claimed in claim 1 whereiniii) the alginate is present in a lesser amount by weight thaniv) the agar.with the proviso that the carrageenan is present in the greatest amount.

11. A textured gel formulation as claimed in claim 1 wherein the gelling agents are present in a ratio, relative to the alginate, of from:ii) kappa carrageenan greater than 1.0 to 6.2,iv) agar - 0.2 to 2.1, andiii) alginate- 1.0.with the proviso that the carrageenan is present in the greatest amount.

12. A textured gel formulation as claimed in claim 11 wherein the gelling agents are present in a ratio, relative to the alginate, of from:ii) kappa carrageenan - 1.6 to 4.8,iv) agar -0.5 to 1.5, andiii) alginate- 1.0.with the proviso that the carrageenan is present in the greatest amount.

13. A textured gel formulation as claimed in claim 11 wherein the kappa carrageenan, agar, and alginate are present in an amount, by weight % of the formulation, of ii) kappa carrageenan from 0.13 to 0.53,iv) agar from 0.02 to 0.18, andiii) alginate from 0.05 to 0.21.with the proviso that the carrageenan is present in the greatest amount.

14. A textured gel formulation as claimed in claim 13 wherein the kappa carrageenan, agar, and alginate are present in an amount, by weight % of the formulation, of ii) kappa carrageenan from 0.20 to 0.41,iv) agar from 0.06 to 0.13, andiii) alginate from 0.05 to 0.21.with the proviso that the carrageenan is present in the greatest amount.

15. A textured gel formulation as claimed in claim 2 whereinix) the sweetener is sucralose and / or sorbitol.

16. A textured gel formulation as claimed in claim 2 whereinx) the emulsifier is lecithin.

17. A textured gel formulation as claimed in claim 2 whereinxi) the oil is sunflower oil.

18. A textured gel formulation as claimed in claim 2 whereinxii) the flavouring is a fruit flavour or menthol.

19. A textured gel formulation as claimed in claim 2 whereinxiii) the thickening agent is xanthan gum.

20. A textured gel formulation as claimed in claim 2 or 19 whereinxiii) the thickening agent is present in an amount, of from 0.1 to 0.4 weight % of the formulation.

21. A textured gel formulation as claimed in claim 1 or 2 wherein the API is a BCS Class I compound.

22. A textured gel formulation as claimed in claim 1 or 2 wherein the API is a BCS Class II compound.

23. A textured gel formulation as claimed in any of the preceding claim 1 or 2 wherein the API is a BCS Class III compound.

24. A textured gel formulation as claimed in claim 21 wherein the API is Cetirizine Dihydrochloride.

25. A textured gel formulation as claimed in claim 24 wherein the formulation comprises ingredients (by weight %) in the range as Table 8a.Table 8aActive / Excipient Min % Max %viii) Water 49.92 to 100.00 vii) pH modifier(s) 0.06 0.71 i) BCS Class I API - e.g. 0.01 3.25 Cetirizine Dihydrochloridevi) Preservative 0.05 0.15 v) Divalent Cation 0.02 0.06 v) Monovalent Cation 0.01 0.04 iv) Agar 0.05 0.15 ii) Carrageenan 0.16 0.49 iii) Alginate 0.07 0.21 xii) Flavouring 0.01 2.60 ix) Sweetener(s) 0.01 12.00xiii) Thickening Agent 0.10 0.4026. A textured gel formulation as claimed in claim 25 wherein the formulation comprises ingredients (by weight %) in the range as Table 8b.Table 8bActive / Excipient Min % Max %viii) Water 71.31 to 100.00 vii) Citric Acid 0.09 0.14 vii) Sodium Citrate 0.26 0.40 i) Cetirizine Dihydrochloride 0.02 2.50 vi) Potassium Sorbate 0.07 0.12 v) Magnesium Chloride 0.03 0.05 v) Potassium Chloride 0.01 0.03 iv) Agar Agar 0.07 0.12 ii) Kappa Carrageenan 0.23 0.38 iii) Sodium Alginate 0.11 0.16 xii) Flavouring 0.01 2.00 ix) Sucralose 0.01 0.03 ix) Sorbitol 0.00 8.78xiii) Xanthan Gum 0.10 0.4027. A textured gel formulation as claimed in claim 24 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 8c or Table 8d.Table 8cActive / Excipient Mass (g) Percentage (%) viii) Water 39.329 98.32 vii) Citric Acid 0.047 0.12 vii) Sodium Citrate 0.135 0.34 i) Cetirizine Dihydrochloride 0.010 0.03 vi) Potassium Sorbate 0.038 0.10 v) Magnesium Chloride 0.015 0.04 v) Potassium Chloride 0.006 0.02 iv) Agar Agar 0.040 0.10 ii) Kappa Carrageenan 0.127 0.32 iii) Sodium Alginate 0.055 0.14 xii) Flavouring – Menthol 0.070 0.18 ix) Sucralose 0.008 0.02 xiii) Xanthan Gum 0.120 0.30Total 40.000 100.00 orTable 8dActive / Excipient Mass (g) Percentage (%) viii) Water 36.427 91.07 vii) Citric Acid 0.045 0.11 vii) Sodium Citrate 0.129 0.32 i) Cetirizine Dihydrochloride 0.010 0.03 vi) Potassium Sorbate 0.037 0.09 v) Magnesium Chloride 0.015 0.04 v) Potassium Chloride 0.006 0.02 iv) Agar Agar 0.037 0.09 ii) Kappa Carrageenan 0.117 0.29 iii) Sodium Alginate 0.053 0.13 xii) Flavouring - Blood 0.070 0.18 Orange or Grapeix) Sucralose 0.008 0.02 ix) Sorbitol 2.926 7.32 xiii) Xanthan Gum 0.120 0.30Total 40.000 100.0028. A textured gel formulation as claimed in claim 22 wherein the API is Ibuprofen Sodium.

29. A textured gel formulation as claimed in claim 28 wherein the formulation comprises ingredients (by weight %) in the range as Table 9a.Table 9aActive / Excipient Min % Max %viii) Water 49.47 to 100.00 i) BCS Class II API - e.g. 0.36 1.95 Ibuprofen Sodiumvi) Preservative 0.06 0.16v) Divalent Cation 0.02 0.06v) Monovalent Cation 0.01 0.04 vii) pH modifier(s) 0.08 1.00 iv) Agar 0.06 0.16 ii) Carrageenan 0.18 0.49 iii) Alginate 0.04 0.12 xii) Flavouring 0.01 2.60 ix) Sweetener(s) 0.00 12.00xiii) Thickening Agent 0.10 0.4030. A textured gel formulation as claimed in claim 29 wherein the formulation comprises ingredients (by weight %) in the range as Table 9b.Table 9bActive / Excipient Min % Max %viii) Water 70.67 to 100.00 i) Ibuprofen Sodium 0.51 1.50 vi) Potassium Sorbate 0.08 0.12 v) Magnesium Chloride 0.03 0.05 v) Potassium Chloride 0.01 0.03 vii) Sodium Bicarbonate 0.39 0.59 vii) Citric Acid 0.12 0.18 iv) Agar Agar 0.08 0.12 ii) Kappa Carrageenan 0.25 0.38 iii) Sodium Alginate 0.06 0.09 xii) Flavouring 0.01 2.00 ix) Sucralose 0.01 0.03 ix) Sorbitol 0.00 8.79xiii) Xanthan Gum 0.10 0.4031. A textured gel formulation as claimed in claim 30 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out Table 9c or Table 9d.Table 9cActive / Excipient Mass (g) Percentage (%)viii) Water 39.033 97.58 i) Ibuprofen Sodium 0.256 0.64 vi) Potassium Sorbate 0.040 0.10 v) Magnesium Chloride 0.015 0.04 v) Potassium Chloride 0.008 0.02 vii) Sodium Bicarbonate 0.195 0.49 vii) Citric Acid 0.06 0.15 iv) Agar Agar 0.040 0.10 ii) Kappa Carrageenan 0.125 0.31 iii) Sodium Alginate 0.030 0.08 xii) Flavouring – Menthol 0.072 0.18 ix) Sucralose 0.006 0.02 xiii) Xanthan Gum 0.120 0.30Total 40.000 100.00 orTable 9dActive / Excipient Mass (g) Percentage (%)viii) Water 36.104 90.26 i) Ibuprofen Sodium 0.256 0.64 vi) Potassium Sorbate 0.040 0.10 v) Magnesium Chloride 0.015 0.04 v) Potassium Chloride 0.008 0.02 vii) Sodium Bicarbonate 0.195 0.49 vii) Citric Acid 0.06 0.15 iv) Agar Agar 0.040 0.10 ii) Kappa Carrageenan 0.125 0.31 iii) Sodium Alginate 0.030 0.08 xii) Flavouring - Blood 0.072 0.18 Orange or Grapeix) Sucralose 0.006 0.02 ix) Sorbitol 2.929 7.32 xiii) Xanthan Gum 0.120 0.30Total 40.000 100.0032. A textured gel formulation as claimed in claim 23 wherein the API is Metformin Hydrochloride.

33. A textured gel formulation as claimed in claim 32 wherein the formulation comprises ingredients (by weight %) in the range as Table 10a.Table 10aActive / Excipient Min % Max %viii) Water 48.56 to 100.00 vi) Preservative 0.05 0.14 v) Divalent Cation 0.01 0.05 v) Monovalent Cation 0.01 0.04 vii) pH modifier(s) 0.03 0.85 iv) Agar 0.05 0.14 ii) Carrageenan 0.16 0.44 iii) Alginate 0.04 0.12 ix) Sweetener(s) 0.00 12.00 xi) Oil 0.20 0.55 x) Emulsifier 0.20 0.55 i) Metformin Hydrochloride 0.70 3.90 xii) Flavouring 0.01 2.60xiii) Thickening Agent 0.10 0.4034. A textured gel formulation as claimed in claim 33 wherein the formulation comprises ingredients (by weight %) in the range as Table 10b.Table 10bActive / Excipient Min % Max %viii) Water 69.37 to 100.00 vi) Potassium Sorbate 0.07 0.11 v) Magnesium Chloride 0.02 0.04 v) Potassium Chloride 0.01 0.03 vii) Citric Acid 0.04 0.06 iv) Agar Agar 0.07 0.11 ii) Kappa Carrageenan 0.23 0.34 iii) Sodium Alginate 0.06 0.09 ix) Sorbitol 0.00 8.43 xi) Sunflower Oil 0.28 0.42 x) Lecithin 0.28 0.42 i) Metformin Hydrochloride 1.00 3.00 xii) Flavouring 0.01 2.00 ix) Sucralose 0.01 0.03xiii) Xanthan Gum 0.10 0.4035. A textured gel formulation as claimed in claim 34 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out Table 10c or Table 10d.Table 10cActive / Excipient Mass (g) Percentage (%)viii) Water 38.237 95.59 vi) Potassium Sorbate 0.035 0.09 v) Magnesium Chloride 0.014 0.04 v) Potassium Chloride 0.006 0.02 vii) Citric Acid 0.020 0.05 iv) Agar Agar 0.038 0.10 ii) Kappa Carrageenan 0.118 0.30 iii) Sodium Alginate 0.030 0.08 xi) Sunflower Oil 0.150 0.38 x) Lecithin 0.150 0.38 i) Metformin Hydrochloride 1.000 2.50 xii) Flavouring – Menthol 0.074 0.19 ix) Sucralose 0.008 0.02 xiii) Xanthan Gum 0.120 0.30Total 40.000 100.00 orTable 10dActive / Excipient Mass (g) Percentage (%)viii) Water 35.453 88.63 vi) Potassium Sorbate 0.035 0.09 v) Magnesium Chloride 0.014 0.04 v) Potassium Chloride 0.006 0.02 vii) Citric Acid 0.020 0.05 iv) Agar Agar 0.037 0.09ii) Kappa Carrageenan 0.113 0.28iii) Sodium Alginate 0.030 0.08 ix) Sorbitol 2.810 7.03 xi) Sunflower Oil 0.141 0.35 x) Lecithin 0.141 0.35 i) Metformin Hydrochloride 1.000 2.50 xii) Flavouring - Blood 0.072 0.18 Orange or Grapeix) Sucralose 0.008 0.02 xiii) Xanthan Gum 0.120 0.30Total 40.000 100.00

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